This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Over the last few years we have solved several structures of the extracellular region of the mammalian epidermal growth factor receptor (sEGFR). Based on our, and others work, we have proposed a model for teh ligand induced dimerization of this receptor that has important implications in understanding both the normal activation of this receptor, and for how to inhibit the aberrant activation seen in numerous cancerous tumors. We now propose to (a) expand our study of the structural basis for inactivation of sEGFR by clinically relevant antibodies, (b) continue our studies of the structural basis of ligand-induced dimerization of sEGFR (c) bring the same structural detail to the invertebrate EGFRs, where our biochemical data suggest that there may be significant differences in both the inactive and active conformations o f the extracellular region of the insect receptors,(d) determine the structure of the Drosophilia EGFR (DER) inhibitor, Argos, and understand the nature of its interactions with DER ligands, (e) begin a series of new investigations of macromolecular complexes in a number of intracellular signaling pathways, including novel phosphoinositide binding proteins and large GTPases.